Note: Descriptions are shown in the official language in which they were submitted.
RJB/~.1133
~ ~9~
1 PROCESS FOR THE PREPARATION OF PENAM DERIVATIVES
This invention relates to a process for the
preparation of antibacterially active penam derivatives
having a ~X-methoxy substituent.
The present invention provides a process for the
preparation of a penam derivative of formula (I):
OCH3 CH
R .NH - ~ -S 1 3
I ~ CH3 (I)
~ N ~
O \ 2
C02R
wherein RA is hydrogen or a group of formula (Ia):
. R.~H.C0- (Ia)
.~
~Z~;~959
~ 2 --
1 wherein X is -C02Rl, or S03Rl; R is Cl_6 alkyl, aryl,
or heterocyclyl; Rl i~ hydrogen, or a pharmaceutically
acceptable salt-forming ion or ester-forming radical,
and R2 represents hydrogen or a pharmaceutically
acceptable salt-forming ion or in vivo hydrolysable
ester-forming radical; which process comprises reacting
a compound of formula (II):
(O)nSR (O)
. ~ m
R~.NH ~-S CH3
I ~ CH3 (II)
/
CO2RY
wherein RB is a removable acyl group which protects
the amino function or a group of formula (IIa):
R.CIH.CO- (IIa)
wherein Y is -CO2RX or -S03RX; n is one and m is zero
or one; R is as defined with respect to formula (I)
above and wherein any reactive groups may be protected;
Rx represents an ester-forming radical, RY represents
hydrogen, a salt-forming radical or a carboxyl-blocking
group, and R3 represents an alkyl, benzyl, or aryl
group; with methanol and thereafter if necessary
carrying out one or more of the following steps:
(i) removal of any blocking or protecting group;
(ii) converting a compound wherein m is one to the
compound wherein m is zero;
12~295~
1 (iii) converting a group Rx into a group Rl;
(iv) converting the product to a pharmaceutically
acceptable salt or ester thereof.
Suitahle examples of the group R include Cl_6
alkyl; an optionally substituted 5-membered
heterocyclic ring containing one or two heteroatoms
selected from oxygen, sulphur and nitrogen; phenyl;
mono-substituted phenyl where the substituent is
halogen, hydroxy, Cl_6 alkoxy, nitro, amino, Cl_6
lo alkyl, Cl_6 haloalkyl, C1_6 alkylcarbonyloxy, or Cl_6
alkyl sulphonylamino (for example -NHS02CH3); or
di-substituted phenyl where the substituents are
selected from hydroxy, halogen, methoxy, acetoxy and
amino.
Suitably R is phenyl; mono substituted phenyl
where the substituent is fluorine, chlorine, hydroxy,
methoxy, nitro, amino, acetoxy or trifluoromethyl; or
di-substituted phenyl where the substituents are
selected from acetoxy, hydroxy, and methoxy.
Suitable Cl_6 alkyl groups for the groups R and
include methyl, ethyl, n- and iso-propyl, n-, iso_,
sec- and tert-butyl.
Suitable 5-membered heterocyclic rings for the
group R include furyl, thienyl, oxazolyl, thiazolyl,
isoxazolyl, iso-thiazolyl, imidazolyl; each such group
may be substituted by various groups for example
halogen, hydroxy, amino, or Cl_6 alkyl. Particular
examples of such groups include 2- or 3- thienyl and
2-aminothiazolyl.
95~
-- 4
1 Speci~ic examples of the group R include phenyl,
2- or 3- thienyl, p-hydroxyphenyl, p-aminophenyl and
p-acetoxyphenyl.
Suitable acyl groups which protect the amino
function for RB include, for example, the
benzyloxycarbonyl group.
Suitable pharmaceutically acceptable salt-forming
ions for the groups R1 and R2 include metal salts, eg
aluminium, alkali metal salts such as sodium or
potassium, alkaline earth metal salts such as calcium
or magnesium, and ammonium or substituted ammonium
salts, for example those with lower alkylamines such as
triethylamine, hydroxy-lower alkylamines such as
2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or
tri-(2-hydroxyethyl)-amine, cycloalkylamines such as
bicyclohexylamine, or with procaine, dibenzylamine,
N,N-dibenzylethylenediamine, l-ephenamine, N-ethyl-
piperidine, N-benzyl-~-phenethylamine, dehydroabeityl-
amine, N,N'-bisdehydroabietylethylenediamine, or bases
of the pyridine type such as pyridine, collidine or
quinoline, or other amines which have been used to form
salts with known penicillins.
The salt-forming ions included within the
definition of the group RY include the above
mentioned ions and also include other salt-forming ions
which are not necessarily pharmaceutically acceptable.
When the group R2 represents a pharmaceutically
acceptable in vivo hydrolysable ester-forming radical,
such esters are those which hydrolyse readily in the
human body to produce the parent acid, and include, for
example, acyloxyalkyl groups such as acetoxymethyl,
)2~5~
1 pivaloyloxymethyl, ~-acetoxyethyl, ~acetoxybenzyl and
~-pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl
groups, such as ethoxycarbonyloxymethyl and ~-ethoxy-
carbonyloxyethyl; dialkylaminoalkyl groups such as
dimethylaminomethyl, dimethylaminoethyl, diethylamino-
methyl or diethylaminoethyl; and lactone groups such as
phthalidyl or dimethoxyphthalidyl.
The group Rl may be any of the ester-forming
radicals as specified for the group R2 and in addition
lo Rl may represent other pharmaceutically acceptable
ester-forming groups such as alkyl, aryl or aralkyl
groups any of which may be substituted. ~xamples of
such groups include:
a) Cl_6 alkyl such as methyl, ethyl, n- and iso_
propyl, n-, sec-, iso_ and tert-butyl;
b) substituted Cl_6 alkyl wherein the substituent is
at least one of: chloro, bromo, fluoro, nitro,
C1_6alkoxy, Cl_6alkoxycarbonyl, cyano,
Cl_6alkylthio, Cl_6alkylamino;
c) phenyl, benzyl or substituted phenyl or benzyl
wherein the substituent is at least one of chloro,
bromo, fluoro, Cl_6alkyl, Cl_6alkoxy,
Cl_6alkanoyl, C1_6alkoxycarbonyl, nitro or
di-(Cl_6)alkylamino.
Preferred ester-forming radicals Rl include Cl_6
alkyl, benzyl, phthalidyl, indanyl, phenyl and mono-,
di-, and tri-~Cl_6)-alkyl substituted phenyl such as
o-, m-, or p-~ethylphenyl, ethylphenyl, n- or
lso-propylphenyl, or n-, sec-, iso_ or t-butylphenyl.
~2~il2959
-- 6 --
1 Suitable carboxyl-blocking groups for ~he group
RY are those which may be readily removed from the
carboxylic acid under conventional conditions at a
later stage oE the reaction. Such groups include
benzyl, p-methoxybenzyl, 2,4,6-trimethylbenzyl,
3,5-di-t-butyl-4-hydroxybenzyl, benzoylmethyl, p-nitro-
benzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-
tribromoethyl, allyl, acetonyl, diphenylmethyl, tri-
phenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methyl-
thiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl,
pentachlorophenyl, p-toluenesulphonylethyl,
methoxymethyl, a silyl, stannyl or phosphorus-
containing group, an oxime radical of formula ~N=CHR
where R is aryl or heterocyclic, or an in vivo
hydrolysable ester radical such as defined above.
The carboxyl group may be regenerated from any of
the above esters by usual methods appropriate to the
particular RY group, for example, acid- and base-
catalysed hydrolysis, or by enzymically- catalysed
hydrolysis, or by hydrogenation.
When it is desired to produce a compound of
formula (I) wherein the group Rl is hydrogen or a
salt-forming ion, by the process of this invention, a
compound of formula (II) is employed wherein Rx is a
blocking group. For the preparation of a compound of
formula (I) wherein Rl is a pharmaceutically acceptable
ester-forming radical, a compound of formula (II) is
employed wherein Rx represents the desired Rl group.
When the group R represents p-hydroxyphenyl, it
may if desired be protected by means of a group which
is readily removed chemically after the process of the
:~L202~9
1 invention. Such protectinq groups include
benzyloxycarbonyl.
Suitable examples of the alkyl group R3 include
C1_6 alkyl groups such as methyl, ethyl, n- or
iso-propyl, and n-, sec-, lso_, or tert-butyl groups.
A preferred al~yl group for R3 is methyl.
Suitable examples of the aryl group R3 include
phenyl, optionally substituted with Cl_6 alkyl, C1_6
alkoxy, halogen, or nitro. Preferred aryl groups for
R3 include phenyl, o-, m- or ~-methylphenyl, o-, _- or
p-nitrophenyl, in particular p-methylphenyl.
A suitable temperature range for the process of
this invention is greater than ambient temperature,
conveniently 50C to 100C, preferably at the reflux
temperature of the solvent system employed. The time
required for the reaction depends on the temperature
- and the reagents employed. Generally, the reaction is
complete within one hour. The methanol used in the
process is conveniently employed as a solvent for the
reaction mixtures. Other compatible co solvents may be
additionally used if desired, for example, tetrahydro-
furan.
The starting material for the process of this
invention, ie compound of formula (II) above may
suitably be prepared by oxidation of a compound of
formula ~III):
1~29S9
1 SR S CH3
RB-NH ~ ~ CH3
~_ N ~ (III)
C02R
wherein RB, RY and R3 are as defined with respect
to formula (II) above.
The oxidation is suitably brought about using an
organic per-acid as the oxidising agent. Suitable
acids include m-chloroperbenzoic acid and equivalent
reagents.
It is normal to carry out the oxidation in an
inert solvent such as methylene chloride or the like at
an ambient or depressed temperature, for example at
-20C to +20C, more suitably at -12C to +5C, for
example at about 0C.
The compound of formula (III) above where RB is
not hydrogen, is disclosed, although not claimed, in US
Patent Wo 3,965,093. It may be prepared by acylation,
under conventional conditions of the compound (III)
where RB is hydrogen, ie a 6-amino compound of
formula (IV) or a salt or ester thereof:
SR3
0 ~ (IV)
C02H
~2~2959
.
1 wherein R3 is as defined with respect to formula (II)
above. Compounds of formula (IV) may be prepared from
a Schiff's base derivative as described in US Patent No
3,965,093 or may be prepared by reacting a thiooxime
compound of formula (V):
R3-S-N ~ S ~ 3
C02H (V )
(where R3 is as defined with respect to formula (II)
above) with a tri(alkyl)phosphine or
tri(aryl)phosphine, followed by treatment with an acid
catalyst such as silica gel. That process is described
in US Patent No 4,119,778 and in J Amer Chem Soc, 1977,
_ , 5504.
The compounds of formula ~Il wherein RA is not
hydrogen, which are prepared by the process of this
invention have good antibacterial activity, as
disclosed in British Patents Nos 1,538,051 and
1,538,0S2. The compounds of formula (I) wherein RA
is hydrogen are useful as chemical intermediates.
The following Examples illustrate the process
of this invention.
gll.~2~59
. ~,.
-- 10 --
~xample 1
Oxidation of Benz~ -methylthio-613-phen~lacetamido~
penicillanate
A solution of benzyl ~-meth~lthio-6!3-phen~l-
acetamidopenicillanate in methylene dichloride at
ice-bath temperature was treated with a solution of
m-chloroperbenzoic acid (1.1 eq) in methylene
dichloride. After stirring at that temperature for 75
mins, the reaction mixture was washed with saturated
aqueous sodium hydrogen carbonate, dried ~MgSO4) and
evaporated. Chromatographic purification o~ the
residue gave among others products, benzyl 6~-methyl-
thio-613-phen~lacetamidopenicillanate-1-(S)-l-oxide (1)
benzyl ~-methylsulphinyl-6~-phenylacetamido-
penicillanate (2) and benzyl 6~-methylsulphinyl-613-
phenylacetamidopenicillanate-l-(S)-l-oxide (3). These
gave the following spectroscopic characteristics;
The oxide (1)
~ (CDC13) 1.06 and 1.57 (each 3H, s, gem Me2) 2.16
(3H, s, Me), 3.61 (2H, s, Ph.CH2.CO), 4.61 (lH, s,
C.CH.N), 4.86 (lH, s, C.CH.S), 5.18 (2H, AB~, J 12Hz,
CO2.CH2.Ph), 6.72 (lH, s, CO.NH.C), 7.30 and 7.34 (each
5H, s, aromatic H).
The penicillanate (2)
max (CH2C12) 3400 (N-H), 1785 (~-lactam C=0), 1745
~ester C=0) and 1690 (amide C=0) cm~l, S (CDC13) 1.32
and 1.39 (each 3H, s, gem Me2), 2.68 (3H, s, S(O)Me),
3.63 (2H, s, Ph.CH2C0), 4.49 (lH, s, N.CH.CO2), 5.13
(2H, s, CO2.CH2Ph), 6.01 (lH, s, C.CH.S), 7.35 and 7.37
(each 5H, s, aromatic H), and 7.51 (lH, s, CO.NH.C).
!
~v2sss
The oxide (3)
~ max ( CHC13) 3450 and 3380 (N-H), 1790 (13-lactam
C-0), 1755 (ester C=0), 1680 (amide C=0), and 1055
(S=0) Cm~1 S(CDC13) major isomer 1.06 and 1.58 (each
3H, S, ~ Me2), 2.57 (3H, S, S(O)Me), 3.59 (2H, S,
Ph.CH2.CO), 4.74 (1H, S, N.CH,CO2), 5.20 (2H, ~Bq, J
12HZ, CO2 CH2.Ph), 5.22 (1H, S, C.CHS), 7.23 and 7.33
(each 5H, s, aromatic H), and 7.46 (lH, s, CO.NH.C).
Example 2
Thermol~sis of the Sulphoxide (2) in Methanol
Benzyl 6~-methylsulphinyl-613-phenylacetamido-
penicillanate (0.033g, 0.068 mmol) (prepared as in
Example l) was dissolved in methanol (2. 5 ml) and the
solution heated under reflux. A~ter 3 hours, when all
starting material had been depleted (t~l.c), the
solvent was removed under reduced pressure and the
residue chromatoqraphed on silica gel to give benzyl
6~-methOXY-6I3-PhenY1aCetamidOPeniCi11anate (0.028 g,
90%) which was identical in all respects with an
authentic sample (t.l.c., n.m.r., i.r.) (CDC13) 1.33
(6H, S, ~ Me2), 3.37 (3H, S, OMe), 3.60 (2H, s,
Ph.CH2.C0), 4.37 (lH, s, C.CH.N), 5.16 (2H, S,
CO2.CH2.Ph)r 5.46 (lH, s, C.CH.S), 6.50 (lH, s,
CO.NH.C), and 7.30 and 7.35 (each 5H, S, aromatic H).
~Z~:95~
.
- 12 -
Example 3
Thermolysis of the Sulphoxide (3) in Methanol
Benzyl 6~-methylsulphinyl-613-phenylacetamido-
penicillanate-l-~S)-l-oxide (2.23g, 4.44 x 10-3 mol)
(prepared as in Example 1) was taken up in methanol
(100 ml) and the resul'ing solution heated under
reflux. The progress of the reaction was monitored by
t.l.c. and after 3.75 hours, when no starting material
remained, the solvent was removed in vacuo and the
residue chromatographed on silica gel to afford benæyl
6~-methoxy-613-phenyl-acetamidopenicillanate-
l-(S)-l-oxide (1.98g, 95%), m.p. 123-124C (from
CHC13-Et20~, V max (CH2C12) 3400 and 3300 (N-H), 1790
(~-lactam C=0), 1755 (ester C=0), 1685 ~amide C=0), and
1060 (S=0) cm~l, ~ (CDC13) 1.05 and 1.~9 (each 3H, s,
gem Me2), 3.34 (3H, s, OMe), 3.63 ~2H, s, Ph.CH2.CO),
4.64 (lH, s, N.CH.CO2), 4.93 (lH, s, C.CH.S), 5.21 (2H,
ABq, J 12Hz, CO2.CH2.Ph), 7.05 (lH, s, CO.NH.C), and
7.29 and 7.35 (each 5H, s, aromatic H), m/e 470 (M+)
and 91 (C7H7+t base peak). (Found : C, 61.44; H, 5.70;
N, 5.80; S, 6.44; M+, 470.1532. C24H26N206S requires C,
61.26; H, 5.57; N, 5.95; S, 6.81%; Ml 470.1511).
-120Z959
- 13 -
Example 4
Oxidation of Benzyl 613-[2-(2-methylphenoxycarbonyl)-2~
(3-thienyl)acetamido]-6~-(4-methylpheny])thio-
penicillanate (7)
Benzyl 613-[2-(2-methylphenoxycarbonyl)-2-
(3-thienyl)acetamido]-6~-(4-methylphenyl)thio-
penicillanate in methylene dichloride at 0C was
treated with a solution of m-chloroperbenzoic acid (1.1
eq) in methylene dichloride. ~lork-up as described in
Example 1 gave, among other products benzyl
613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-
acetamido]-6~-(4-methylphenyl)-sulphinylpenicillanate
~4) and benzyl 613-[2-(2-methylphenoxycarbonyl)-2-
(3-thienyl)acetamido]~ (4-methyl~henyl)sulphinyl-
penicillanate-l-oxide (5). These gave the following
spectral characteristics;
The penicillanate (4)
~ (CDC13) inter alia 1.30 (s, gem Me2), 2.10 and
2.37 (each s~ 2xPh.Me), 4.44 (s, N.CH.C), 4.89
(S.CO.CH.CO), 5.17 (s, CO2CH2.Ph), 6.07 (s, C.CH.S),
and 6.9-7.6 (m, CO.NH.C and aromatic H).
The oxide (5)
;~ max (CHC13) 3240 (N-H, 1795 (13-lactam C=0), 1745
(ester C=0), and 1680 (amide C=0) cm~l, ~ (CDC13) 1.10
and 1.24 (each 3H, s, ~ e2), 2.12 and 2.32 (each 3H,
s, 2xPh.Me), 4.66 (lH, s, N.CH.C), 5.20 (lH, s,
CO.CH.CO), 5.24 (2H, ABq, J 12 Hz, CO2CH2.Ph), 5.35
(lH, s, C.CH.S), and 7.0-7.5 (17H, m, CO.NH.C and
aromatic H).
s9
-- 14 -
Example 5
Ther~olysis of the Sulphoxide (4) in Methanol
A solution of benzyl 6~-[2-(2-methylpheno~y-
carbonylj-2-(3-thienyl)-acetamido]-6~-(4-methylphenyl)-
sulphinylpenicillanate (prepared as in Example 4) in
methanol was heated under reflux. After 7.5 hours, the
solvent was evaporated in vacuo and the residue
chromatoyraphed on silica gel to give, among other
products, benzyl 6t3-[2-(2-methylphenoxycarbonyl)-2-(3-
thienyl)acetamido]-6~-methoxypenicillanate. It
exhibited the following characteristics;
V max (CH2C12) 3400 (N-H), 1780 (~-lactam C=0), 1745
(ester C=0), and 1700 (amide C=0) cm~l, ~(CDC13) 1.34
(6H, s, gem Me2), 2.12 (3H, s, Ph.Me), 3.46 (3H, s,
OMe), 4.47 (lH, s, N.CH.CO2), 5.08 (lH, s, C.CH.S),
5.23 (2HI s, C~2.CH2.Ph), 5.64 (lH, s, CO2.CH.CO),
6.9-7.7 (12H, m, aromatic H), and 7.85 (lH, s,
CO.NH.C).
Example 6
Thermolysis of the Sulphoxide (5) in Methanol
Benzyl 6~-[2-(2-methylphenoxycarbonyl-2-(3-
thienyl)acetamido3-6~-(4-methylphenyl)sulphinylpeni-
cillanate-l-oxide (0.059g, 8.22x10-5 mol) (prepared as
in Example 4) was taken up in methanol (5 ml) and the
solution heated under reflux. After 12 hours, the
solvent was removed under reduced pressure and the
residue chromatographed on silica gel to give, as the
first eluted product benzyl-6~-methoxy-6t3-[2-(2-methyl-
phenoxycarbonyl)-2-(3-thienyl)acetamido]penicillanate-
1-(S)-l-oxide (0.016g, 32%), V max (CHC13) 3400 (N-H),
1790 (13-lactam C=0), 1745 br (ester C=0's), and 1690
i~Q29S9
- 15 -
(amide C=0) cm~l, (CDC13), 1.06 and 1.58 (each 3H, s,
gem Me2), 2.03 and 2~11 (3H, each s, CO2.Ph.Me), 3.45
and 3.46 (3H, each s, OMe), 4.61 (lH, s, N.CH.CO2),
~.95 and 4.98 (lH, each s, C.CH.S), 5.01 and 5.08 (lH,
each s, CO2.CH.C0), 5.17 (lEI, d, J llHz, CO2.CHH.Ph),
5.31 (lH, dd, J 11 and 1.5Hz, CO2.CHH.Ph),6.98 and 8.02
(lH, each s, CO.NH.C), and 7.0-7.6 (12H,m, aromatic H).
The second eluted product was benzyl 6~-methoxy-
6~-[2-methoxycarbonyl-2-(3-thienyl)acetamido]peni-
cillanate-l-(S)-l-oxide (0.009g, 20~ ~ax (CHC13)
3390 (N-H), 1790 (13-lactam C=0), 1740 and 1730 (ester
C=0) and 1690 (amide C=0~ cm~l, S(CDC13) 1.05 and 1.57
(each 3H, s, gem Me2), 3.42 and 3.45 (3H, each s, OMe),
3 77 (3H, s, CO2Me), 4.60 and 4.63 (lH, each s,
N.CH.CO2), 4.71 and 4.83 (lH, each s, C.CH.S), 4.91 and
4.94 (lH, each s, CO2.CH.CO), 5.17 (lH, dd, J 12 and
2Hz, C02.CHH.Ph), 5.31 (lH, d, J 12Hz, CO2.CHH.Ph),
7.02 and 8.17 (lH, each s, CO.NH.C), and 7.1-7.5 (8H,
m, aromatic H).
Example 7
Oxidation of Benzyl-6!3-[2-(2-methylphenoxycarbonyl)-2-
(3-thienyl)acetamido]-6~-methylthiopenicillanate
The above penicillanate in methylene dichloride at
0~C was treated with a solution of m-chloroperbenzoic
acid (1.1 eq) in methylene dichloride. Work-up as
described in Example 1 gave, among other products,
benzyl 613-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)
acetamido]-6d~methylsulphinylpenicillanate (6) and
benzyl 6~-[2-(2-methylphenoxycarbonyl)-2-(3-thienyl)-
acetamido]-~-methylsulphinylpenicillanate-l-oxide
(7). These gave the following characteristics;
~2!11 Z~5g
.
- 15 -
The penicillanate (6)
~ (CDC13) 1.3 br (6H, s, gem Me2), 2.05 (3H, s,
Ph.Me), 2.70 (3H, s, S(0)Me), 4.50 (lH, s, N.CH.C),
5.05 (lH, s, CO.CH.C0), 5.10 (2H, s, CO2.CE~2Ph), 6.03
(lH, s, C.CH.S), 7.0-7.6 (12H, m, aromatic H), and ~.30
br (lH, s, CO.NH.C).
The oxide (7)
~ (CDC13) 1.00 and 1.50 (each 3H, s, gem Me2), 2.05
(3H, s, Ph.Me), 2.53 and 2.74 (3H, each s, S(0)Me),
4.65 and 4.78 (lH, each s, N.CH.C), 5.00-5.35 (4H, m,
CO2.C~2.Ph, CO.CH.C0, and C.CH.S), and 6.90-7.60 (lH,
m, C~.NH.C and aromatic H).
Example 8
Thermolysis of the Sulphoxide (6)
Benzyl 613-~2-(2-methylphenoxycarbonyl)-2-(3-
thienyl)acetamido]-6 -methylsulphinylpenicillanate
(0.090g, 0.144 mmol) ~prepared as in Example 7) was
dissolved in methanol (5 ml) and the solution heated
under reflux for 1 hour. The solvent was then-removed
under reduced pressure and the residue chromato~raphed
on silica gel to give Benzyl 6a-methoxy-6!3-[2-(2-
methylphenoxycarbonyl)-2-(3-thienyl)acetamido]-
penicillanate (0.075g, 90%).
Example 9
Oxidation of the mono-Sulphoxide (1)
Benzyl 6a methylthio-6!3-phenylacetamido-
penicillanate-l-(S)-l-oxide (0.179g) in methylene
dichloride (10 ml) at 0C was treated with m-chloroper-
benzoic acid (0.076 g) in methylene dichloride for 45
mins. Work-up and chromatography, as described in
Example 1 gave the bis-sulphoxide (3) (0.052 g).
2959
- 17 -
Example 10
Reaction of Benzyl 6p~- Methoxy-6,!3[2(2-methyl-
phenoxycarbonyl)-2-(3-thienyl) acetamido] penicillanate
-l-(S)-l-oxide with Phosphorous Tribromide
Benzyl-6~-methoxy-6~-[2-(2-methylphenoxycarbonyl)-
2-(3-thienyl)acetamido]penicillanate-1-(S)-l-oxide
(0.063g, 0.103 mmol) (prepared as in Example 6) was
taken up in dimethylformamide (1 ml), the solution
cooled in an ice bath, and phosphorous tribromide
(0.043 g, 0.159 mmol) added in one portion. Progress
of the reaction was monitored (t.l.c) and after 55
mins, when all reactant had been depleted, the reaction
mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium hydrogen carbonate (2x),
followed by saturated brine. The separated organic
layer was dried (r1gso4)~ and evaporated to give as
residue benzyl 6~-methoxy-6!3-[2-(2-methylphenoxy-
carbonyl)-2-(3-thienyl)acetamido]penicillanate (0.058g,
95%) which was identical in all respects (t.l.c.,
n.m.r., i.r.) with an authentic sample.
Example 11
Reaction of the Sulphoxide (3) with Methanol
Benzyl ~-methylsulphinyl-6!3-phenylacetamido-
penicillanate-l-(S)-l-oxide (prepared as in Example 1)
was taken up in methanol and the homogeneous solution
allowed to stand at 25C. Progress of the reaction was
monitored by t.l.c. and after 12 days, when no reactant
remained, the methanol ~as removed under reduced
pressure. Examination of the residue (n.m.r. i.r. and
t.l.c) showed only the presence of benzyl 6~-methoxy-
6~3-phenylacetamidopenicillanate-1-(S)-l-oxide.
~959
18 -
Example 12
Reaction of the Sulphoxide (3) with Methanol in the
presence of Triethylamine
A solution oE benzyl ~-methylsulphinyl-6!3-phenyl-
acetamido-l-(S)l-oxide (prepared as in Example 1)
(0,050 9, 9.96x10-5 mmol) in methanol (3 ml) was
stirred with triethylamine (0.01g, 14 ~1, 9.96x10-5
mmol) at room temperature. After 24 hours the methanol
was removed in vacuo the residue taken up in ethyl
acetate and washed with dilute aqueous hydrochloric
acid. The separated organic phase was dried (MgSO4)
and evaporated to give a residue which was subjected to
purification by silica gel column chromatography. The
first-eluted product was identical in all respect
(i.r., n.m.r., t.l.c.) to the [6~-methoxypenicillin
sulphoxide of Example 11 (0.019 g, 40~). The
second~eluted component was methyl 6~-methoxy-6~-
phenylacetamidopenicillanate-l-(S)-l-oxide (0.008g,
23%); max (CHC13) 3400 (N-H), 1790 (!3-lactam C=0),
1750 (ester C=0) and 1680 (amide C=0)cm~l, (CDC13)
1.23 and 1.66 (each 3H, s, gem Me2), 3.40 (3H, s, OMe),
3.66 (2H, s, Ph.CH2.C0), 3.80 (3H, s, CO3Me), 4.59 (lH,
s, N.CH.C), 4.98 (lH, s, C.CH.S), 6.50 br (lH, s,
CO.NH.C), and 7.2-7.4 (5H, m, aromatics).
